Sphingosine-1-phosphate (hereinafter referred to as “S1P”) is a physiologically active lipid which is generated when sphingolipids (typified by sphingomyelin) are metabolized in cells. S1P is known to have a wide variety of actions such as cell differentiation induction, cell growth stimulation, cell motility inhibition and apoptosis inhibition, and is also known to show physiological actions such as angiogenesis, bradycardia induction, inflammatory cell activation and platelet activation (Non-patent Document 1).
As SIP receptors, the following 5 subtypes have been reported: Edg-1(S1P1), Edg-3(S1P3), Edg-5(S1P2), Edg-6(S1P4) and Edg-8(S1P5) (Non-patent Document 2).
Among these subtypes, Edg-1(S1P1) is highly expressed in immunocytes (e.g., T cells, dendritic cells) and vascular endothelial cells, suggesting that Edg-1(S1P1) contributes deeply to S1P-stimulated T cell migration (Non-patent Document 3), mast cell migration (Non-patent Document 4), T and B cell egress from lymphoid organs (Non-patent Document 5) and angiogenesis (Non-patent Document 6), and is involved in autoimmune diseases such as Crohn's disease, irritable colitis, Sjogren's syndrome, multiple sclerosis and systemic lupus erythematosus, as well as other diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, age-related macular degeneration, etc.
Thus, ligands for Edg-1(S1P1) would be effective for treatment or prevention of these diseases.
Edg-1(S1P1) ligands previously known include certain types of thiophene derivatives (Non-patent Document 7), phosphoric acid derivatives (Patent Documents 1 and 2, Non-patent Documents 8 and 9) and thiazolidine derivatives (Patent Document 3), carboxylic acid derivatives (Patent Documents 4, 5, 6 and 8, Non-patent Documents 10 and 11), amino group-containing derivatives (Patent Document 7), and pyrrole derivatives (Patent Document 9).    Patent Document 1: WO2002-18395    Patent Document 2: JP 2003-137894 A    Patent Document 3: JP 2002-332278 A    Patent Document 4: WO2002-092068    Patent Document 5: WO2003-105771    Patent Document 6: WO2004-058149    Patent Document 7: WO2004-103279    Patent Document 8: WO2005-1058848    Patent Document 9: WO2005-123677    Non-patent Document 1: J Biol. Chem. 2004, 279: 20555, FASEB J 2002, 16: 625, Proceedings of the Japanese Society for Immunology 2003, 33: 2-J-W30-20-P    Non-patent Document 2: Pharmacol Res 2003, 47: 401    Non-patent Document 3: FASEB J 2002, 16:1874    Non-patent Document 4: J Exp Med 2004, 199: 959    Non-patent Document 5: Nature 2004, 427: 355    Non-patent Document 6: J Clin Invest 2000, 106: 951, Biocchim Biophys Acta 2002, 1582: 222    Non-patent Document 7: J Biol Chem 2004, 279: 13839    Non-patent Document 8: Bioorg Med Chem Lett 2003, 13: 3401    Non-patent Document 9: J Med. Chem. 2004, 47: 6662    Non-patent Document 10: J Med. Chem. 2005, 48: 6169    Non-patent Document 11: J Biol. Chem. 2005; 280: 9833